(R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid as a free acid shows the structure illustrated in Formula II:

(R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid use in the preparation of a medicament for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the enzyme TAFIa (activated thrombin-activatable fibrinolysis inhibitor), has been disclosed in WO 2005/105781.
The enzyme TAFIa is produced for example through thrombin activation from the thrombin-activatable fibrinolysis inhibitor zymogen (TAFI). The enzyme TAFI is also referred to as plasma procarboxypeptidase B, procarboxypeptidase U or procarboxypeptidase R and is a proenzyme similar to carboxypeptidase B (L. Bajzar, Arterioscler. Thromb. Vasc. Biol. 2000, pages 2511-2518).
During formation of a clot, thrombin is generated as the final product of the coagulation cascade and induces conversion of soluble plasma fibrinogen to an insoluble fibrin matrix. At the same time, thrombin activates the endogenous fibrinolysis inhibitor TAFI. Activated TAFI (TAFIa) is thus produced during thrombus formation and lysis from the zymogen TAFI through the action of thrombin; thrombomodulin in a complex with thrombin increases this effect about 1250-fold. TAFIa cleaves basic amino acids at the carboxy end of fibrin fragments. The loss of carboxy-terminal lysines as binding sites for plasminogen then leads to inhibition of fibrinolysis. Efficient inhibitors of TAFIa prevent the loss of these high-affinity lysine binding sites for plasminogen and, in this way, assist endogenous fibrinolysis by plasmin: TAFIa inhibitors have profibrinolytic effects.
In order to maintain hemostasis in the blood, mechanisms which lead to the clotting of blood and to the breaking up of clots have developed; these are in equilibrium. If a disturbed equilibrium favors coagulation, fibrin is produced in larger quantities, so that pathological processes of thrombus formation may lead to serious pathological states in humans.
Just like excessive coagulation may lead to serious pathological states caused by thrombosis, an antithrombotic treatment entails the risk of unwanted bleeding through disturbance of the formation of a necessary hemostatic plug. Inhibition of TAFIa increases endogenous fibrinolysis—without influencing coagulation and platelet aggregation—i.e. the disturbed equilibrium is shifted in favor of fibrinolysis. It is thus possible both to counter the buildup of a clinically relevant thrombus, and to increase the lysis of a pre-existing clot. On the other hand, buildup of a hemostatic plug is not impaired, so that a hemorrhagic diathesis is probably not to be expected (Bouma et al., J. Thrombosis and Haemostasis, 1, 2003, pages 1566-1574).
Inhibitors of TAFIa have already been described in the International Applications WO03/013526 and WO2005/105781. Processes for preparation are disclosed in WO2010/130718.
3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid bishydrochloride salt and its pharmacological activities have been disclosed in WO2005/105781. The bishydrochloride salt of 3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid and the free acid of 3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid have the disadvantage to occur as amorphous solids. Thus, said hydrochloride acid salts as well as said free acid cannot be purified by crystallization. Additionally, it was found that the free acid of 3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid is hygroscopic. Further it was found that (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid is chemically not stable under elevated temperature and humidity. A degradation of the molecule could be observed and the enantiomeric purity of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid is reduced within a short time. Therefore, (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid is not suitable for the development in a pharmaceutical formulation.
Hygroscopicity is the ability of a substance to attract and hold water molecules from the surrounding environment through either absorption or adsorption with the adsorbing or absorbing material becoming physically ‘changed,’ somewhat, increase in volume, stickiness, or other physical characteristic changes of the material as water molecules become ‘suspended’ between the material's molecules in the process. Therefore hygroscopic compounds are generally very unfavorable for use in solid pharmaceutical compositions.
It is an object of the present invention to find crystalline salts of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid with reduced absorption or adsorption of water molecules from the surrounding environment and are chemically stable. It has been found that crystalline sodium salts of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid have favorable reduced absorption or adsorption of water molecules from the surrounding environment and are chemically stable.